Extracellular vesicles from oligodendrocytes restore antigen-specific immune tolerance in mice models of multiple sclerosis.

Background: Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. Results: We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. Conclusions: Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis.

Since extracellular vesicles (EVs) were discovered in 1983 in sheep reticulocytes samples, they have gradually attracted scientific attention and become a topic of great interest in the life sciences field. EVs are small membrane particles, released by virtually every cell that carries a variety of functional molecules. Their main function is to deliver messages to the surrounding area in both physiological and pathological conditions. Initially, they were thought to be either cell debris, signs of cell death, or unspecific structures. However, accumulating evidence support a theory that EVs are a universal mechanism of communication. Thanks to their biological characteristics and functions, EVs are likely to represent a promising strategy for obtaining pathogen information, identifying therapeutic targets and selecting specific biomarkers for a variety of diseases, such as autoimmune diseases.

Autoimmune diseases are conditions that emerge from abnormal immune responses to natural parts of the body. Extracellular vesicles (EVs) are membranous structures found in almost all types of cells. Because EVs often transport “cargo” between cells, their ability to crosstalk may be an important communication pathway within the body. The pathophysiological role of EVs is increasingly recognized in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, Type 1 diabetes, and autoimmune thyroid disease. EVs are considered as biomarkers of these diseases. This article outlines existing knowledge on the biogenesis of EVs, their role as messegers in cellular communication and the function in T/B cell differentiation and maturation, and focusing on their potential application in autoimmune diseases.

MicroRNAs (miRNAs) are small, non-coding RNAs involved in immune response regulation. Specific miRNAs have been linked to the development of various autoimmune diseases; however, their contribution to the modulation of CNS-directed cellular infiltration remains unclear. In this study, we found that miR-23b, in addition to its reported functions in the suppression of IL-17-associated autoimmune inflammation, halted the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by directly inhibiting the migration of pathogenic leukocytes to the CNS. We demonstrated that miR-23b was specifically decreased during the acute phase of EAE and that overexpression of miR-23b resulted in a defect in leukocyte migration and strong resistance to EAE. Furthermore, we found that miR-23b suppressed leukocyte migration of EAE by targeting CCL7, a chemokine that attracts monocytes during inflammation and metastasis. Finally, in the adoptive transfer model, miR-23b reduced the severity of EAE by inhibiting the migration of pathogenic T cells to the CNS rather than diminishing the encephalitogenesis of T cells. Taken together, our results characterize a novel aspect of miR-23b function in leukocyte migration, and they identify miR-23b as a potential therapeutic target in the amelioration of MS and likely other autoimmune diseases.